Despite years of effort, no effective acute phase treatment has been discovered for traumatic brain injury. One impediment to successful drug development is entangled secondary injury pathways. Here we show that protein S, a natural multifunctional protein that regulates coagulation, inflammation, and apoptosis, is able to reduce the extent of multiple secondary injuries in traumatic brain injury, and therefore improve prognosis. Mice subjected to controlled cortical impact were treated acutely (10-15 minutes post-injury) with a single dose of either protein S (1 mg/kg) or vehicle phosphate buffered saline via intravenous injection. At 24 hours post-injury, compared to the non-treated group, the protein S treated group showed substantial improvement of edema and fine motor coordination, as well as mitigation of progressive tissue loss. Immunohistochemistry and western blot targeting caspase-3, B-cell lymphoma 2 (Bcl-2) along with terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay revealed that apoptosis was suppressed in treated animals. Immunohistochemistry targeting CD11b showed limited leukocyte infiltration in the protein S-treated group. Moreover, protein S treatment increased the ipsilesional expression of aquaporin-4, which may be the underlying mechanism of its function in reducing edema. These results indicate that immediate intravenous protein S treatment after controlled cortical impact is beneficial to traumatic brain injury prognosis.